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Abstract:

Provided herein are bicyclic compounds and methods of synthesis thereof.
The compounds provided herein are useful for the treatment, prevention,
and/or management of various neurological disorders. Compounds provided
herein inhibit uptake of endogenous monoamines, such as dopamine,
serotonin and norepinephrine (e.g., from the synaptic cleft) and modulate
one or more monoamine transporter. Pharmaceutical formulations containing
the compounds are also provided.

26. The method of claim 24, wherein the neurodegenerative disease is
Parkinson's disease.

27. The method of claim 24, wherein the sleep disorder is sleep apnea.

28. The method of claim 24, wherein the pain is neuropathic pain.

29. The method of claim 14, wherein said monoamine transporter is a
serotonin transporter (SERT), a dopamine transporter (DAT), a
norepinephrine transporter (NET), or a combination thereof.

Description:

[0001] This application claims priority to U.S. Provisional Application
No. 61/138,062, filed Dec. 16, 2008, the entirety of which is
incorporated herein by reference.

1. FIELD

[0002] Provided herein are compounds useful as triple reuptake inhibitors,
compositions comprising the compounds, and methods of their use.

2. BACKGROUND

[0003] Monoamine neurotransmitters have been implicated in the body's
response to neurological disorders such as pain and depression.
Norepinephrine (NE) and serotonin (5-HT) are monoamine neurotransmitters
originating in the brain and projecting diffusely throughout the central
nervous system. 5-HT and NE are reported to be involved in modulating
pain transmission from the spinal cord to the brain and also governing
the body's moods and responses to stress.

[0004] Depression refers to an abnormal mood or a collection of symptoms
that constitute a psychiatric disorder. Symptoms of depression include
disturbances in mood and affect (depressed mood, diminished interest and
pleasure in activities), bodily function (weight and appetite changes,
psychomotor disturbances, sleep disturbances, fatigue, and loss of
energy), and cognitive processes (feelings of worthlessness and guilt,
concentration difficulties, indecisiveness, thoughts of death or suicide,
and possibly delusions/hallucinations). These symptoms vary in intensity,
duration and frequency and permit classification of depression into
different classes. Other symptoms of major depressive episodes include
crying spells, self-pity, hopelessness, irritability, brooding,
diminished self-esteem, decreased libido, nihilism, social withdrawal,
memory impairment, feelings of inadequacy, and pessimism.

[0005] It has been reported that electrical stimulation of certain brain
regions releases 5-HT and NE, which are believed to produce an analgesia
in both animals and humans. Conversely, it has been reported that
depletion of serotonin in the rat results in an enhanced response to
pain. There also appears to be synergistic actions between NE and 5-HT in
modulating pain sensation. Studies in the rat show that the analgesia
from exogenously administered 5-HT can be blocked by depleting NE in the
spinal cord.

[0006] Common antidepressants increase synaptic availability of biogenic
amines by blocking their major means of physiological inactivation, which
involves transport or reuptake into nerve terminals. Examples include
"dual" action agents that inhibit the reuptake of both NE and 5-HT (e.g.,
venlafaxine and milnacipram), selective serotonin reuptake inhibitors
(SSRIs) (e.g., fluoxetine and sertraline), and norepinephrine reuptake
inhibitors (e.g., Reboxetine). A major drawback to all of these agents is
the therapeutic lag associated with their use--patients must take the
drug for up to 3 weeks to achieve clinically meaningful symptomatic
relief. Furthermore, a significant number of patients do not respond to
current therapies at all. For example, it is currently estimated that up
to thirty percent (30%) of clinically diagnosed cases of depression are
resistant to all forms of current drug therapy. Consequently, there is a
significant need for effective treatments of various neurological
disorders.

[0010] In another embodiment, provided herein is a method of inhibiting
binding of a monoamine transporter ligand to a monoamine transporter,
such as serotonin transporter, dopamine transporter and norepinephrine
transporter. The method comprises contacting the monoamine transporter
and a compound of the invention. In an exemplary embodiment, the
monoamine transporter ligand is a monoamine, such as serotonin, dopamine
and norepinephrine.

[0011] Also provided herein is a method of inhibiting the activity of at
least one monoamine transporter, such as serotonin transporter, dopamine
transporter and norepinephrine transporter. The method comprises
contacting the monoamine transporter and a compound provided herein.

[0012] Also provided herein is a method of inhibiting uptake of at least
one monoamine, such as serotonin, dopamine and norepinephrine, by a cell.
The method comprises contacting the cell with a compound of the
invention. In an exemplary embodiment, the cell is a brain cell, such as
a neuronal cell or a glial cell.

4. BRIEF DESCRIPTION OF FIGURES

[0013] FIG. 1 illustrates the levels of tested compounds in brain
following an oral administration at a dose of 10 mg/kg.

[0014]FIG. 2 illustrates the ratio of brain and plasma levels of the
tested compounds following an oral administration at a dose of 10 mg/kg.

[0016] As used herein, and unless otherwise indicated, the term "alkyl"
refers to a linear or branched saturated monovalent hydrocarbon radical,
wherein the alkyl may optionally be substituted with one or more
substituents. The term "alkyl" also encompasses both linear and branched
alkyl, unless otherwise specified. In certain embodiments, the alkyl is a
linear saturated monovalent hydrocarbon radical that has 1 to 20
(C1-20), 1 to 15 (C1-15), 1 to 12 (C1-12), 1 to 10
(C1-10), or 1 to 6 (C1-6) carbon atoms, or branched saturated
monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15
(C3-15), 3 to 12 (C3-12), 3 to 10 (C3-10), or 3 to 6
(C3-6) carbon atoms. As used herein, linear C1-6 and branched
C3-6 alkyl groups are also referred as "lower alkyl." Examples of
alkyl groups include, but are not limited to, methyl, ethyl, propyl
(including all isomeric forms), n-propyl, isopropyl, butyl (including all
isomeric forms), n-butyl, isobutyl, t-butyl, pentyl (including all
isomeric forms), and hexyl (including all isomeric forms). For example,
C1-6 alkyl refers to a linear saturated monovalent hydrocarbon
radical of 1 to 6 carbon atoms or a branched saturated monovalent
hydrocarbon radical of 3 to 6 carbon atoms.

[0017] As used herein, and unless otherwise specified, the term "alkenyl"
refers to a linear or branched monovalent hydrocarbon radical, which
contains one or more, in one embodiment, one to five, carbon-carbon
double bonds. The alkenyl may be optionally substituted one or more
substituents. The term "alkenyl" also encompasses radicals having "cis"
and "trans" configurations, or alternatively, "E" and "Z" configurations,
as appreciated by those of ordinary skill in the art. As used herein, the
term "alkenyl" encompasses both linear and branched alkenyl, unless
otherwise specified. For example, C2-6 alkenyl refers to a linear
unsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or a
branched unsaturated monovalent hydrocarbon radical of 3 to 6 carbon
atoms.

[0018] In certain embodiments, the alkenyl is a linear monovalent
hydrocarbon radical of 2 to 20 (C2-20), 2 to 15 (C2-15), 2 to
12 (C2-12), 2 to 10 (C2-10), or 2 to 6 (C2-6) carbon
atoms, or a branched monovalent hydrocarbon radical of 3 to 20
(C3-20), 3 to 15 (C3-15), 3 to 12 (C3-12), 3 to 10
(C3-10), or 3 to 6 (C3-6) carbon atoms. Examples of alkenyl
groups include, but are not limited to, ethenyl, propen-1-yl,
propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

[0019] As used herein, and unless otherwise specified, the term "alkynyl"
refers to a linear or branched monovalent hydrocarbon radical, which
contains one or more, in one embodiment, one to five, carbon-carbon
triple bonds. The alkynyl may be optionally substituted one or more
substituents. The term "alkynyl" also encompasses both linear and
branched alkynyl, unless otherwise specified. In certain embodiments, the
alkynyl is a linear monovalent hydrocarbon radical of 2 to 20
(C2-20), 2 to 15 (C2-15), 2 to 12 (C2-12), 2 to 10
(C2-10), or 2 to 6 (C2-6) carbon atoms, or a branched
monovalent hydrocarbon radical of 3 to 20 (C3-20), 3 to 15
(C3-15), 3 to 12 (C3-12), 3 to 10 (C3-10), or 3 to 6
(C3-6) carbon atoms Examples of alkynyl groups include, but are not
limited to, ethynyl (--C≡CH) and propargyl (--CH2C≡CH).
For example, C2-6 alkynyl refers to a linear unsaturated monovalent
hydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturated
monovalent hydrocarbon radical of 3 to 6 carbon atoms.

[0020] As used herein, and unless otherwise specified, the term
"cycloalkyl" refers to a cyclic saturated bridged and/or non-bridged
monovalent hydrocarbon radical, which may be optionally substituted one
or more substituents as described herein. In certain embodiments, the
cycloalkyl has from 3 to 20 (C3-20), from 3 to 15 (C3-15), from
3 to 12 (C3-12), from 3 to 10 (C3-10), or from 3 to 7
(C3-7) carbon atoms. Examples of cycloalkyl groups include, but are
not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl, decalinyl, and adamantyl.

[0021] As used herein, and unless otherwise specified, the terms
"heteroalkyl," "heteroalkenyl," and "heteroalkynyl" refer to alkyl,
alkenyl, and alkynyl, respectively, wherein one or more carbon atoms are
replaced with heteroatoms.

[0022] As used herein, and unless otherwise specified, the term
"heteroatom" refers to any atom other than carbon or hydrogen. In some
embodiments, the term "heteroatom" refers to N, O, S, Si, or P. In other
embodiments, the term "heteroatom" refers to N, O, or S.

[0023] As used herein, and unless otherwise specified, the term "aryl"
refers to a monocyclic aromatic group and/or multicyclic monovalent
aromatic group that contain at least one aromatic hydrocarbon ring. In
certain embodiments, the aryl has from 6 to 20 (C6-20), from 6 to 15
(C6-15), or from 6 to 10 (C6-10) ring atoms. Examples of aryl
groups include, but are not limited to, phenyl, naphthyl, fluorenyl,
azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl
also refers to bicyclic or tricyclic carbon rings, where one of the rings
is aromatic and the others of which may be saturated, partially
unsaturated, or aromatic, for example, dihydronaphthyl, indenyl, indanyl,
or tetrahydronaphthyl (tetralinyl). In certain embodiments, aryl may also
be optionally substituted with one or more substituents.

[0024] As used herein, and unless otherwise specified, the term
"arylalkyl" or "aralkyl" refers to a monovalent alkyl group substituted
with aryl. In certain embodiments, both alkyl and aryl may be optionally
substituted with one or more substituents.

[0026] As used herein, and unless otherwise specified, the term "solvate"
refers to a compound provided herein or a salt thereof, which further
includes a stoichiometric or non-stoichiometric amount of solvent bound
by non-covalent intermolecular forces. Where the solvent is water, the
solvate is a hydrate.

[0027] As used herein, and unless otherwise specified, the term
"stereoisomer" encompasses all enantiomerically/stereomerically pure and
enantiomerically/stereomerically enriched compounds provided herein.

[0028] As used herein and unless otherwise specified, the term
"stereomerically pure" means a composition that comprises one
stereoisomer of a compound and is substantially free of other
stereoisomers of that compound. For example, a stereomerically pure
composition of a compound having one chiral center will be substantially
free of the opposite enantiomer of the compound. A stereomerically pure
composition of a compound having two chiral centers will be substantially
free of other diastereomers of the compound. A typical stereomerically
pure compound comprises greater than about 80% by weight of one
stereoisomer of the compound and less than about 20% by weight of other
stereoisomers of the compound, greater than about 90% by weight of one
stereoisomer of the compound and less than about 10% by weight of the
other stereoisomers of the compound, greater than about 95% by weight of
one stereoisomer of the compound and less than about 5% by weight of the
other stereoisomers of the compound, or greater than about 97% by weight
of one stereoisomer of the compound and less than about 3% by weight of
the other stereoisomers of the compound.

[0029] As used herein and unless otherwise indicated, the term
"stereomerically enriched" means a composition that comprises greater
than about 55% by weight of one stereoisomer of a compound, greater than
about 60% by weight of one stereoisomer of a compound, greater than about
70% by weight, or greater than about 80% by weight of one stereoisomer of
a compound.

[0030] As used herein, and unless otherwise indicated, the term
"enantiomerically pure" means a stereomerically pure composition of a
compound having one chiral center. Similarly, the term "enantiomerically
enriched" means a stereomerically enriched composition of a compound
having one chiral center.

[0031] As used herein, and unless otherwise indicated, the terms "treat,"
"treating" and "treatment" refer to the eradication or amelioration of a
disease or disorder, or of one or more symptoms associated with the
disease or disorder. In certain embodiments, the terms refer to
minimizing the spread or worsening of the disease or disorder resulting
from the administration of one or more prophylactic or therapeutic agents
to a subject with such a disease or disorder. In some embodiments, the
terms refer to the administration of a compound provided herein, with or
without other additional active agent, after the onset of symptoms of the
particular disease.

[0032] As used herein, and unless otherwise indicated, the terms
"prevent," "preventing" and "prevention" refer to the prevention of the
onset, recurrence or spread of a disease or disorder, or of one or more
symptoms thereof. In certain embodiments, the terms refer to the
treatment with or administration of a compound provided herein, with or
without other additional active compound, prior to the onset of symptoms,
particularly to patients at risk of disease or disorders provided herein.
The terms encompass the inhibition or reduction of a symptom of the
particular disease. Patients with familial history of a disease in
particular are candidates for preventive regimens in certain embodiments.
In addition, patients who have a history of recurring symptoms are also
potential candidates for the prevention. In this regard, the term
"prevention" may be interchangeably used with the term "prophylactic
treatment."

[0033] As used herein, and unless otherwise specified, the terms "manage,"
"managing," and "management" refer to preventing or slowing the
progression, spread or worsening of a disease or disorder, or of one or
more symptoms thereof. Often, the beneficial effects that a subject
derives from a prophylactic and/or therapeutic agent do not result in a
cure of the disease or disorder. In this regard, the term "managing"
encompasses treating a patient who had suffered from the particular
disease in an attempt to prevent or minimize the recurrence of the
disease.

[0034] As used herein, and unless otherwise specified, a "therapeutically
effective amount" of a compound is an amount sufficient to provide a
therapeutic benefit in the treatment or management of a disease or
disorder, or to delay or minimize one or more symptoms associated with
the disease or disorder. A therapeutically effective amount of a compound
means an amount of therapeutic agent, alone or in combination with other
therapies, which provides a therapeutic benefit in the treatment or
management of the disease or disorder. The term "therapeutically
effective amount" can encompass an amount that improves overall therapy,
reduces or avoids symptoms or causes of disease or disorder, or enhances
the therapeutic efficacy of another therapeutic agent.

[0035] As used herein, and unless otherwise specified, a "prophylactically
effective amount" of a compound is an amount sufficient to prevent a
disease or disorder, or prevent its recurrence. A prophylactically
effective amount of a compound means an amount of therapeutic agent,
alone or in combination with other agents, which provides a prophylactic
benefit in the prevention of the disease. The term "prophylactically
effective amount" can encompass an amount that improves overall
prophylaxis or enhances the prophylactic efficacy of another prophylactic
agent.

[0036] As used herein, and unless otherwise specified, the term "subject"
is defined herein to include animals such as mammals, including, but not
limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,
cats, rabbits, rats, mice and the like. In specific embodiments, the
subject is a human.

[0037] As used herein, and unless otherwise specified, the term "monoamine
transporter ligand" refers to any compound, which binds to a monoamine
transporter. Ligands include endogenous monoamines, which are the natural
ligands for a given monoamine transporter as well as drug molecules and
other compounds, such as synthetic molecules known to bind to a
particular monoamine transporter. In one example, the ligand includes a
radioisotope, such as tritium or is otherwise (e.g., fluorescently)
labeled. It is within the abilities of the skilled person to select an
appropriate ligand for a given monoamine transporter. For example, known
ligands for the dopamine transporter include dopamine and WIN35428, known
ligands for the serotonin transporter include 5-hydroxytryptamine
(serotonin) and citalopram, and ligands for the norepinephrine
transporter include norepinephrine and nisoxetine.

[0038] As used herein, and unless otherwise specified, the term
"neurological disorder" refers to any condition of the central or
peripheral nervous system of a mammal. The term "neurological disorder"
includes, but is not limited to, neurodegenerative diseases (e.g.,
Alzheimer's disease, Parkinson's disease and amyotrophic lateral
sclerosis), neuropsychiatric diseases (e.g., schizophrenia and anxieties,
such as general anxiety disorder), and affective disorders (e.g.,
depression and attention deficit disorder). Exemplary neurological
disorders include, but are not limited to, MLS (cerebellar ataxia),
Huntington's disease, Down syndrome, multi-infarct dementia, status
epilecticus, contusive injuries (e.g., spinal cord injury and head
injury), viral infection induced neurodegeneration, (e.g., AIDS,
encephalopathies), epilepsy, benign forgetfulness, closed head injury,
sleep disorders, depression (e.g., bipolar disorder), dementias, movement
disorders, psychoses, alcoholism, post-traumatic stress disorder and the
like. "Neurological disorder" also includes any condition associated with
the disorder. For instance, a method of treating a neurodegenerative
disorder includes methods of treating loss of memory and/or loss of
cognition associated with a neurodegenerative disorder. An exemplary
method would also include treating or preventing loss of neuronal
function characteristic of neurodegenerative disorder. "Neurological
disorder" also includes any disease or condition that is implicated, at
least in part, in monoamine (e.g., norepinephrine) signaling pathways
(e.g., cardiovascular disease).

[0039] As used herein, and unless otherwise specified, the term "affective
disorder" includes depression, attention deficit disorder, attention
deficit disorder with hyperactivity, bipolar and manic conditions, and
the like. The terms "attention deficit disorder" (ADD) and "attention
deficit disorder with hyperactivity" (ADDH), or attention
deficit/hyperactivity disorder (AD/HD), are used herein in accordance
with the accepted meanings as found in the Diagnostic and Statistical
Manual of Mental Disorders, 4th Ed., American Psychiatric
Association (1997) (DSM-IV®).

[0040] As used herein, and unless otherwise specified, the term
"depression" includes all forms of depression including, but not limited
to, major depressive disorder (MDD), bipolar disorder, seasonal affective
disorder (SAD) and dysthymia. "Major depressive disorder" is used herein
interchangeably with "unipolar depression" and "major depression."
"Depression" may also includes any condition commonly associated with
depression, such as all forms of fatigue (e.g., chronic fatigue syndrome)
and cognitive deficits.

[0041] As used herein, and unless otherwise specified, the terms
"obsessive-compulsive disorder," "substance abuse," "pre-menstrual
syndrome," "anxiety," "eating disorders" and "migraine" are used herein
in a manner consistent with their accepted meanings in the art. See,
e.g., DSM-IV®. For example, the term "eating disorder," as used
herein, refers to abnormal compulsions to avoid eating or uncontrollable
impulses to consume abnormally large amounts of food. These disorders may
affect not only the social well-being, but also the physical well-being
of sufferers. Examples of eating disorders include, but are not limited
to, anorexia nervosa, bulimia, and binge eating.

[0042] As used herein, and unless otherwise specified, the term "pain"
refers to an unpleasant sensory and emotional experience. The term
"pain," as used herein, refers to all categories of pain, including pain
that is described in terms of stimulus or nerve response, e.g., somatic
pain (normal nerve response to a noxious stimulus) and neuropathic pain
(abnormal response of a injured or altered sensory pathway, often without
clear noxious input); pain that is categorized temporally, e.g., chronic
pain and acute pain; pain that is categorized in terms of its severity,
e.g., mild, moderate, or severe; and pain that is a symptom or a result
of a disease state or syndrome, e.g., inflammatory pain, cancer pain,
AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiac
ischaemia, and diabetic peripheral neuropathic pain (see, e.g.,
Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al.,
eds., 12th ed. 1991); Williams et al., J. of Med. Chem. 42: 1481-1485
(1999), herein each incorporated by reference in their entirety). "Pain"
is also meant to include mixed etiology pain, dual mechanism pain,
allodynia, causalgia, central pain, hyperesthesia, hyperpathia,
dysesthesia, and hyperalgesia. In addition, The term "pain" includes pain
resulting from dysfunction of the nervous system: organic pain states
that share clinical features of neuropathic pain and possible common
pathophysiology mechanisms, but are not initiated by an identifiable
lesion in any part of the nervous system.

[0043] The term "somatic pain," as used herein, refers to a normal nerve
response to a noxious stimulus such as injury or illness, e.g., trauma,
burn, infection, inflammation, or disease process such as cancer, and
includes both cutaneous pain (e.g., skin, muscle or joint derived) and
visceral pain (e.g., organ derived).

[0044] The term "neuropathic pain," as used herein, refers to a
heterogeneous group of neurological conditions that result from damage to
the nervous system. The term also refers to pain resulting from injury to
or dysfunctions of peripheral and/or central sensory pathways, and from
dysfunctions of the nervous system, where the pain often occurs or
persists without an obvious noxious input. This includes pain related to
peripheral neuropathies as well as central neuropathic pain. Common types
of peripheral neuropathic pain include diabetic neuropathy (also called
diabetic peripheral neuropathic pain, or DN, DPN, or DPNP), post-herpetic
neuralgia (PHN), and trigeminal neuralgia (TGN). Central neuropathic
pain, involving damage to the brain or spinal cord, can occur following
stroke, spinal cord injury, and as a result of multiple sclerosis, and is
also encompassed by the term. Other types of pain that are meant to be
included in the definition of neuropathic pain include, but are not
limited to, pain from neuropathic cancer pain, HIV/AIDS induced pain,
phantom limb pain, and complex regional pain syndrome.

[0045] The term also encompasses the common clinical features of
neuropathic pain including, but not limited to, sensory loss, allodynia
(non-noxious stimuli produced pain), hyperalgesia and hyperpathia
(delayed perception, summation, and painful aftersensation). Pain is
often a combination of nociceptive and neuropathic types, for example,
mechanical spinal pain and radiculopathy or myelopathy.

[0046] As used herein, and unless otherwise specified, the term "acute
pain" refers to the normal, predicted physiological response to a noxious
chemical, thermal or mechanical stimulus typically associated with
invasive procedures, trauma and disease. It is generally time-limited,
and may be viewed as an appropriate response to a stimulus that threatens
and/or produces tissue injury. The term also refers to pain which is
marked by short duration or sudden onset.

[0047] As used herein, and unless otherwise specified, the term "chronic
pain" encompasses the pain occurring in a wide range of disorders, for
example, trauma, malignancies and chronic inflammatory diseases such as
rheumatoid arthritis. Chronic pain may last more than about six months.
In addition, the intensity of chronic pain may be disproportionate to the
intensity of the noxious stimulus or underlying process. The term also
refers to pain associated with a chronic disorder, or pain that persists
beyond resolution of an underlying disorder or healing of an injury, and
that is often more intense than the underlying process would predict. It
may be subject to frequent recurrence.

[0048] As used herein, and unless otherwise specified, the term
"inflammatory pain" is pain in response to tissue injury and the
resulting inflammatory process. Inflammatory pain is adaptive in that it
elicits physiologic responses that promote healing. However, inflammation
may also affect neuronal function. Inflammatory mediators, including
PGE2 induced by the COX2 enzyme, bradykinins, and other substances,
bind to receptors on pain-transmitting neurons and alter their function,
increasing their excitability and thus increasing pain sensation. Much
chronic pain has an inflammatory component. The term also refers to pain
which is produced as a symptom or a result of inflammation or an immune
system disorder.

[0049] As used herein, and unless otherwise specified, the term "visceral
pain" refers to pain which is located in an internal organ.

[0050] As used herein, and unless otherwise specified, the term "mixed
etiology pain" refers to pain that contains both inflammatory and
neuropathic components.

[0051] As used herein, and unless otherwise specified, the term "dual
mechanism pain" refers to pain that is amplified and maintained by both
peripheral and central sensitization.

[0052] As used herein, and unless otherwise specified, the term
"causalgia" refers to a syndrome of sustained burning, allodynia, and
hyperpathia after a traumatic nerve lesion, often combined with vasomotor
and sudomotor dysfunction and later trophic changes.

[0053] As used herein, and unless otherwise specified, the term "central
pain" refers to pain initiated by a primary lesion or dysfunction in the
central nervous system.

[0054] As used herein, and unless otherwise specified, the term
"hyperesthesia" refers to increased sensitivity to stimulation, excluding
the special senses.

[0055] As used herein, and unless otherwise specified, the term
"hyperpathia" refers to a painful syndrome characterized by an abnormally
painful reaction to a stimulus, especially a repetitive stimulus, as well
as an increased threshold. It may occur with allodynia, hyperesthesia,
hyperalgesia, or dysesthesia.

[0056] As used herein, and unless otherwise specified, the term
"dysesthesia" refers to an unpleasant abnormal sensation, whether
spontaneous or evoked. In certain embodiments, dysesthesia include
hyperalgesia and allodynia.

[0057] As used herein, and unless otherwise specified, the term
"hyperalgesia" refers to an increased response to a stimulus that is
normally painful. It reflects increased pain on suprathreshold
stimulation.

[0058] As used herein, and unless otherwise specified, the term
"allodynia" refers to pain due to a stimulus that does not normally
provoke pain.

[0059] As used herein, and unless otherwise specified, the term "Diabetic
Peripheral Neuropathic Pain" (DPNP), also called diabetic neuropathy, DN
or diabetic peripheral neuropathy), refers to chronic pain caused by
neuropathy associated with diabetes mellitus. The classic presentation of
DPNP is pain or tingling in the feet that can be described not only as
"burning" or "shooting" but also as severe aching pain. Less commonly,
patients may describe the pain as itching, tearing, or like a toothache.
The pain may be accompanied by allodynia and hyperalgesia and an absence
of symptoms, such as numbness.

[0060] As used herein, and unless otherwise specified, the term
"Post-Herpetic Neuralgia", also called "Postherpetic Neuralgia (PHN)",
refers to a painful condition affecting nerve fibers and skin Without
being limited by a particular theory, it is a complication of shingles, a
second outbreak of the varicella zoster virus (VZV), which initially
causes chickenpox.

[0061] As used herein, and unless otherwise specified, the term
"neuropathic cancer pain" refers to peripheral neuropathic pain as a
result of cancer, and can be caused directly by infiltration or
compression of a nerve by a tumor, or indirectly by cancer treatments
such as radiation therapy and chemotherapy (chemotherapy-induced
neuropathy).

[0062] As used herein, and unless otherwise specified, the term "HIV/AIDS
peripheral neuropathy" or "HIV/AIDS related neuropathy" refers to
peripheral neuropathy caused by HIV/AIDS, such as acute or chronic
inflammatory demyelinating neuropathy (AIDP and CIDP, respectively), as
well as peripheral neuropathy resulting as a side effect of drugs used to
treat HIV/AIDS.

[0063] As used herein, and unless otherwise specified, the term "Phantom
Limb Pain" refers to pain appearing to come from where an amputated limb
used to be. Phantom limb pain can also occur in limbs following paralysis
(e.g., following spinal cord injury). "Phantom Limb Pain" is usually
chronic in nature.

[0064] As used herein, and unless otherwise specified, the term
"Trigeminal Neuralgia (TN)" refers to a disorder of the fifth cranial
(trigeminal) nerve that causes episodes of intense, stabbing,
electric-shock-like pain in the areas of the face where the branches of
the nerve are distributed (lips, eyes, nose, scalp, forehead, upper jaw,
and lower jaw). It is also known as the "suicide disease".

[0065] As used herein, and unless otherwise specified, the term "Complex
Regional Pain Syndrome (CRPS)," formerly known as Reflex Sympathetic
Dystrophy (RSD), refers to a chronic pain condition whose key symptom is
continuous, intense pain out of proportion to the severity of the injury,
which gets worse rather than better over time. The term encompasses type
1 CRPS, which includes conditions caused by tissue injury other than
peripheral nerve, and type 2 CRPS, in which the syndrome is provoked by
major nerve injury, and is sometimes called causalgia.

[0066] As used herein, and unless otherwise specified, the term
"fibromyalgia" refers to a chronic condition characterized by diffuse or
specific muscle, joint, or bone pain, along with fatigue and a range of
other symptoms. Previously, fibromyalgia was known by other names such as
fibrositis, chronic muscle pain syndrome, psychogenic rheumatism and
tension myalgias.

[0067] As used herein, and unless otherwise specified, the term
"convulsion" refers to a neurological disorder and is used
interchangeably with "seizure," although there are many types of seizure,
some of which have subtle or mild symptoms instead of convulsions.
Seizures of all types may be caused by disorganized and sudden electrical
activity in the brain. In some embodiments, convulsions are a rapid and
uncontrollable shaking during which the muscles contract and relax
repeatedly.

[0076] In one embodiment, m is 0. In another embodiment, m is 1. In
another embodiment, m is 2.

[0077] In one embodiment, n is 0. In another embodiment, n is 1. In
another embodiment, n is 2.

[0078] In one embodiment, X is hydrogen. In another embodiment, X is
(C1-C10)alkyl. In another embodiment, X is
(C3-C10)cycloalkyl. In another embodiment, X is
(C3-C10)cycloalkyl-(C1-C10)alkyl. In another
embodiment, X is (C1-C10)alkenyl. In another embodiment, X is
(C1-C10)alkynyl. In another embodiment, X is
(C1-C10)alkoxy. In another embodiment, X is 6 to 10 membered
aryl. In another embodiment, X is (6 to 10 membered
aryl)-(C1-C10)alkyl. In another embodiment, X is --OR1. In
another embodiment, X is heteroalkyl. In another embodiment, X is
heteroalkenyl. In another embodiment, X is heteroalkynyl. In another
embodiment, X is heterocycloalkyl.

[0079] In one embodiment where X is --OR1, R1 is hydrogen. In
another embodiment, R1 is (C1-C10)alkyl. In another
embodiment, R1 is (C1-C10)alkenyl. In another embodiment,
R1 is (C1-C10)alkynyl. In another embodiment, R1 is
(C3-C10)cycloalkyl. In another embodiment, R1 is
(C3-C10)cycloalkyl-(C1-C10)alkyl. In another
embodiment, R1 is(C1-C10)alkoxy. In another embodiment,
R1 is 6 to 10 membered aryl. In another embodiment, R1 is (6 to
10 membered aryl)-(C1-C10)alkyl. In another embodiment, R1
is --SO2(C1-C10)alkyl. In another embodiment, R1 is
--SO2-(6 to 10 membered aryl).

[0080] In one embodiment, Y is halogen. In another embodiment, Y is
--CF3. In another embodiment, Y is --CN. In another embodiment, Y is
--NH2. In another embodiment, Y is --NO2. In another
embodiment, Y is dioxolano. In another embodiment, Y is
(C1-C10)alkyl. In another embodiment, Y is
(C3-C10)cycloalkyl. In another embodiment, Y is
(C1-C10)alkenyl. In another embodiment, Y is
(C1-C10)alkynyl. In another embodiment, Y is
(C1-C10)alkoxy. In another embodiment, Y is
(C3-C10)cycloalkoxy. In another embodiment, Y is --OR2.

[0081] In one embodiment, Z is halogen. In another embodiment, Z is
--CF3. In another embodiment, Z is --CN. In another embodiment, Z is
--NH2. In another embodiment, Z is --NO2. In another
embodiment, Z is dioxolano. In another embodiment, Z is
(C1-C10)alkyl. In another embodiment, Z is
(C3-C10)cycloalkyl. In another embodiment, Z is
(C1-C10)alkenyl. In another embodiment, Z is
(C1-C10)alkynyl. In another embodiment, Z is
(C1-C10)alkoxy. In another embodiment, Z is
(C3-C10)cycloalkoxy. In another embodiment, Z is --OR2.

[0082] In one embodiment, where Y and/or Z are --OR2, R2 is
hydrogen. In another embodiment, R2 is (C1-C10)alkyl. In
another embodiment, R2 is (C1-C10)alkenyl. In another
embodiment, R2 is (C1-C10)alkynyl. In another embodiment,
R2 is (C3-C10)cycloalkyl. In another embodiment, R2
is (C3-C10)cycloalkyl-(C1-C10)alkyl. In another
embodiment, R2 is (C1-C10)alkoxy. In another embodiment,
R2 is 6 to 10 membered aryl. In another embodiment, R2 is (6 to
10 membered aryl)-(C1-C10)alkyl. In another embodiment, R2
is --SO2(C1-C10)alkyl. In another embodiment, R2 is
--SO2-(6 to 10 membered aryl).

[0083] In one embodiment, Y and Z together form a 5 membered cycloalkyl.
In one embodiment, Y and Z together form a 6 membered cycloalkyl. In one
embodiment, Y and Z together form a 7 membered cycloalkyl.

[0084] Any of the combinations of m, n, X, Y, Z, R1 and R2 are
encompassed by this disclosure and specifically provided herein.

[0085] In one embodiment, n is 1. In one embodiment where n is 1, m is 1
or 2.

[0086] In one embodiment, X is hydrogen. In another embodiment, X is
(C1-C10)alkyl. In another embodiment, X is methyl. In another
embodiment, X is ethyl.

[0087] In one embodiment, at least one of Y and Z are halogen. In another
embodiment, Y and Z are both halogen. In another embodiment, Y and Z are
both chloride.

[0088] Specific examples include, but are not limited to, the following
compounds, or pharmaceutically acceptable salt, solvate, or stereoisomers
thereof:

##STR00003##

[0089] It should be noted that if there is a discrepancy between a
depicted structure and a name given that structure, the depicted
structure is to be accorded more weight. In addition, if the
stereochemistry of a structure or a portion of a structure is not
indicated with, for example, bold or dashed lines, the structure or
portion of the structure is to be interpreted as encompassing all
stereoisomers of it.

5.2.1 Synthetic Schemes

[0090] Five and six-membered ring aryl lactones can be synthesized via the
lactone arylation procedures substantially similar to those disclosed in
Malcolm et al., Tetrahedron Lett., 46: 6871 (2005) to give dichloro
analog 2a and 2b. Opening of lactone 2a/2b with lithium methylamide
proceed in excellent yield to give alcohol 3a/3b, which is followed by
borane reduction to give amino alcohol 4a/4b. An alternate procedure
using methylamine in ethanol also provides good results in the
ring-opening step. The procedures are summarized in Scheme 1, below:

##STR00004##

[0091] Amino alcohol 4a/4b are separated by chiral HPLC (e.g.,
AD--2:3:95:0.1 MeOH/EtOH/Hex/DEA) to give enantiomers 5a/b and 6a/b. Each
enantiomer is then cyclized to provide the corresponding 5-5 and 6-5
bicyclic amines. The methylamine is demethylated using neat 1-chloroethyl
chloroformate (CECF) to give 5-5 secondary amines and 6-5 secondary
amines. Separation can be carried out using various methods known in the
art. The procedures are summarized in Scheme 2, below:

##STR00005##

[0092] An alternative route to the racemic 6-5 bicyclic des-methyl amine
(10, Scheme 3) was also developed that started from lactone 2b. Heating
lactone 2b in the presence of potassium phthalimide provides amino acid
7, which can be converted directly to lactam 9 (via intermediate 8) after
heating in KOH. Borane reduction of lactam 9 gave the desired racemic 6-5
desmethyl analog 10.

[0094] 6-5 lactone 2b can be also used as the starting point for the
synthesis of the N-ethyl substituted analogs (i.e., 13, Scheme 5).
Opening of the lactone with ethylamine provides amide-alcohol 11, which
is reduced with borane to give amino alcohol 12. Mesylation of 12 and
intramolecular cyclization provides racemic N-ethyl product 13.

[0096] In various embodiments, provided herein is a method of binding a
compound provided herein to a monoamine transporter. The method comprises
contacting the monoamine transporter and a compound provided herein.

[0097] In other embodiments, provided herein is a method of inhibiting
binding of a monoamine transporter ligand to a monoamine transporter
(such as serotonin transporter, dopamine transporter and norepinephrine
transporter). The method comprises contacting the monoamine transporter
and a compound provided herein. In one embodiment the monoamine
transporter ligand is an endogenous monoamine, such as serotonin,
dopamine or norepinephrine. In another embodiment, the ligand is a drug
molecule or another small molecule known to have binding affinity to a
monoamine transporter. In another embodiment, the monoamine transporter
ligand is a radioactively labeled compound, known to bind to the
monoamine transporter.

[0098] In one embodiment, inhibition of ligand binding is assessed using
an ex vivo binding assay, such as those described herein. In another
embodiment, the compound provided herein inhibits mean binding by between
about 1% and about 100%, between about 10% and about 100%, and between
about 20% and about 90% when compared to vehicle. In one embodiment,
inhibition of mean binding is dose dependent.

5.3.2 Inhibition of Monoamine Transporter Activity

[0099] In various embodiments, provided herein is a method of modulating
(e.g., inhibiting, augmenting) the activity of at least one monoamine
transporter, such as serotonin transporter, dopamine transporter and
norepinephrine transporter. The method comprises contacting the monoamine
transporter and a compound provided herein. In one embodiment, the
monoamine transporter is contacted with a compound provided herein by
administering to a subject a therapeutically effective amount of the
compound provided herein, or a pharmaceutically acceptable salt or
solvate thereof. The subject may be a human. In another embodiment, the
monoamine transporter is dopamine transporter (DAT), serotonin
transporter (SERT), or norepinephrine transporter (NET). In other
embodiments, the compound provided herein inhibits the activity of at
least two different monoamine transporters. Inhibition of monoamine
transporter activity may be measured using assays known in the art.
Exemplary assay methods include, but are not limited to, in vitro
functional uptake assays. In one embodiment, the functional uptake assay
utilizes an appropriate cell-line expressing a desired monoamine
transporter. In other embodiments, the functional uptake assay utilizes
synaptosomes isolated from brain tissue of an appropriate organism. In
other embodiments, inhibition of monoamine transporter activity may be
assessed using receptor binding experiments known in the art, e.g.,
utilizing appropriate membrane preparations. In one embodiment, the assay
involves treatment of a test subject (e.g., a rat) with a compound
provided herein as well as a reference compound, followed by isolation of
brain tissue and ex vivo analysis of receptor occupancy, as described
herein.

5.3.3 Inhibition of Monoamine Uptake

[0100] In some embodiments, provided herein is a method of inhibiting
uptake of at least one monoamine (e.g., dopamine, serotonin,
norepinephrine) by a cell. The method includes contacting the cell with a
compound provided herein. In one embodiment, the cell is a brain cell,
such as a neuron or a glial cell. In one embodiment, inhibition of
monoamine uptake occurs in vivo. In an organism, neuronal uptake (also
termed reuptake) of a monoamine such as dopamine or serotonin may occur,
for example, from the synaptic cleft. Thus, in one embodiment, the
neuronal cell is in contact with a synaptic cleft of a mammal. In another
embodiment, inhibition of monoamine uptake occurs in vitro. In some
embodiments, the cell may be a brain cell, such as a neuronal cell or a
cell-type, which expresses a recombinant monoamine transporter.

[0101] In one embodiment, the compound inhibits uptake of at least two
different monoamines. This can, for example, be shown by performing
various in vitro functional uptake assays utilizing a cell-type, which
simultaneously expresses multiple different monoamine transporters (such
as isolated synaptosomes), or may be shown by using two different cell
types, each expressing a different monoamine transporter, such as a
recombinant dopamine transporter, together with an appropriate, labeled
monoamine. In some embodiments, inhibition of monoamine uptake is
demonstrated when the inhibitor (e.g., a compound provided herein) has an
IC50 of, for example, between about 0.1 nM and about 10 μM,
between about 1 nM and about 1 μM, between about 1 nM and about 500
nM, and between about 1 nM and about 100 nM, in a functional monoamine
uptake assay, such as those described herein below.

5.3.4 Treatment of Neurological Disorders

[0102] In some embodiments, provided herein is a method of treating,
preventing, and/or managing a neurological disorder. Without being
limited by a particular theory, the treatment, prevention, and/or
management is done by inhibiting the activity of at least one monoamine
transporter. The method comprises administering to a patient (e.g.,
human) a therapeutically or prophylactically effective amount of a
composition or compound provided herein, or a pharmaceutically acceptable
salt or solvate thereof. In one embodiment, the patient is a human. In
another embodiment, the compound provided herein inhibits the activity of
at least two different monoamine transporters. For example, the compound
of the invention inhibits the activity of at least two of serotonin
transporter, dopamine transporter and norepinephrine transporter. In some
embodiments, inhibition of monoamine transporter activity may be assessed
by functional monoamine uptake assays as described herein below.

[0103] Demonstration of compound activity can be performed in various
art-recognized animal models. For example, anti-depressant activity of a
compound may be assessed by utilizing an appropriate animal model of
depression such as, but not limited to, the Rat Forced Swim Test, the
Mouse Tail Suspension Test and Rat Locomotor Activity Analyses. The Rat
Forced Swim Test is also suitable for the analysis of compounds having
activities against more than one monoamine transporter (mixed monoamine
transporter activity). For example, an increase in swimming activity is
indicative of serotonin reuptake inhibition, while an increase in
climbing activity is indicative of norepinephrine reuptake inhibition.

[0104] In some embodiments, the compounds provided herein are active in at
least one animal model, which can be used to measure the activity of the
compounds and estimate their efficacy in treating a neuroligal disorder.
For example, when the animal model is for depression (e.g., mean
immobility), the compounds are active when they inhibit mean immobility
by between about 5% and about 90%, between about 10% and about 70%,
between about 10% and about 50%, and between about 15% and about 50% in
at least one animal model, when compared to vehicle. In some embodiments,
the compounds provided herein produce a similar disparity in measured
endpoint between treated animals and animals administered vehicle.

[0105] In other embodiments, provided herein is a method of effecting an
anti-depressant-like effect. The method comprises administering to a
subject (e.g., a mammal) a therapeutically effective amount of a compound
or composition provided herein, or a pharmaceutically acceptable salt or
solvate thereof. Anti-depressant-like effects may be measured using an
animal model of disease, such as those known in the art and those
described herein.

[0110] In one embodiment, the neurological disorder is depression. In
another embodiment, the neurological disorder is anxiety disorder. In
another embodiment, the neurological disorder is pain. In another
embodiment, the neurological disorder is neuropathic pain. In another
embodiment, the neuropathic pain is diabetic neuropathy.

[0111] In one embodiment, the neurological disorder is a neurodegenerative
disease. In one embodiment, the neurodegenerative disease is Parkinson's
disease. In another embodiment, the neurodegenerative disorder is
Alzheimer's disease.

[0112] In one embodiment, the neurological disorder is incontinence, for
example, urinary incontinence. In another embodiment, the neurological
disorder is sexual dysfunction.

[0113] In one embodiment, the neurological disorder is obesity, and the
therapeutically effective amount of compound to supply to a patient is
sufficient so that said patient feels satiated.

[0114] In one embodiment, the compounds described herein treat, prevent,
and/or manage a central nervous disorder, without causing addiction to
said compounds.

[0115] Any suitable route of administration can be employed for providing
the patient with a therapeutically or prophylactically effective dose of
an active ingredient. For example, oral, mucosal (e.g., nasal,
sublingual, buccal, rectal, vaginal), parenteral (e.g., intravenous,
intramuscular), transdermal, and subcutaneous routes can be employed.
Exemplary routes of administration include oral, transdermal, and
mucosal. Suitable dosage forms for such routes include, but are not
limited to, transdermal patches, ophthalmic solutions, sprays, and
aerosols. Transdermal compositions can also take the form of creams,
lotions, and/or emulsions, which can be included in an appropriate
adhesive for application to the skin or can be included in a transdermal
patch of the matrix or reservoir type as are conventional in the art for
this purpose. An exemplary transdermal dosage form is a "reservoir type"
or "matrix type" patch, which is applied to the skin and worn for a
specific period of time to permit the penetration of a desired amount of
active ingredient. The patch can be replaced with a fresh patch when
necessary to provide constant administration of the active ingredient to
the patient.

[0116] The amount to be administered to a patient to treat, prevent,
and/or manage the disorders described herein will depend upon a variety
of factors including the activity of the particular compound employed, or
the ester, salt or amide thereof, the route of administration, the time
of administration, the rate of excretion or metabolism of the particular
compound being employed, the duration of the treatment, other drugs,
compounds and/or materials used in combination with the particular
compound employed, the age, sex, weight, condition, general health and
prior medical history of the patient being treated, and like factors well
known in the medical arts.

[0117] A physician or veterinarian having ordinary skill in the art can
readily determine and prescribe the effective amount required. For
example, the physician or veterinarian could start doses of the compounds
employed at levels lower than that required in order to achieve the
desired therapeutic effect and gradually increase the dosage until the
desired effect is achieved.

[0118] In general, a suitable daily dose of a compound provided herein
will be that amount of the compound which is the lowest dose effective to
produce a therapeutic or prophylactic effect. Such an effective dose will
generally depend upon the factors described above. Generally, oral,
intravenous, intracerebroventricular and subcutaneous doses of the
compounds provided herein for a patient will range from about 0.005 mg
per kilogram to about 5 mg per kilogram of body weight per day. In one
embodiment, the oral dose of a compound provided herein will range from
about 10 mg to about 300 mg per day. In another embodiment, the oral dose
of a compound provided herein will range from about 20 mg to about 250 mg
per day. In another embodiment, the oral dose of a compound provided
herein will range from about 100 mg to about 300 mg per day. In another
embodiment, the oral dose of a compound provided herein will range from
about 10 mg to about 100 mg per day. In another embodiment, the oral dose
of a compound provided herein will range from about 25 mg to about 50 mg
per day. In another embodiment, the oral dose of a compound provided
herein will range from about 50 mg to about 200 mg per day. Each of the
above-recited dosage ranges may be formulated as a single or multiple
unit dosage formulations.

[0119] In some embodiments, the compounds disclosed herein may be used in
combination with one or more second active agents to treat, prevent,
and/or manage disorders described herein. Examples of such second active
agents are also provided herein elsewhere.

5.4 Pharmaceutical Compositions and Dosage Forms

[0120] Pharmaceutical compositions can be used in the preparation of
individual, single unit dosage forms. Pharmaceutical compositions and
dosage forms provided herein comprise a compound provided herein, or a
pharmaceutically acceptable salt, solvate, stereoisomer, clathrate, or
prodrug thereof. Pharmaceutical compositions and dosage forms can further
comprise one or more excipients.

[0121] Pharmaceutical compositions and dosage forms provided herein can
also comprise one or more additional active ingredients. Examples of
optional second, or additional, active ingredients are also disclosed
herein.

[0123] The composition, shape, and type of dosage forms will typically
vary depending on their use. For example, a dosage form used in the acute
treatment of a disease may contain larger amounts of one or more of the
active ingredients it comprises than a dosage form used in the chronic
treatment of the same disease. Similarly, a parenteral dosage form may
contain smaller amounts of one or more of the active ingredients it
comprises than an oral dosage form used to treat the same disease. These
and other ways in which specific dosage forms are used will vary from one
another and will be readily apparent to those skilled in the art. See,
e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,
Easton Pa. (1990).

[0124] In one embodiment, pharmaceutical compositions and dosage forms
comprise one or more excipients. Suitable excipients are well known to
those skilled in the art of pharmacy, and non-limiting examples of
suitable excipients are provided herein. Whether a particular excipient
is suitable for incorporation into a pharmaceutical composition or dosage
form depends on a variety of factors well known in the art including, but
not limited to, the way in which the dosage form will be administered to
a patient. For example, oral dosage forms such as tablets may contain
excipients not suited for use in parenteral dosage forms. The suitability
of a particular excipient may also depend on the specific active
ingredients in the dosage form. For example, the decomposition of some
active ingredients may be accelerated by some excipients such as lactose,
or when exposed to water. Active ingredients that comprise primary or
secondary amines are particularly susceptible to such accelerated
decomposition. Consequently, provided are pharmaceutical compositions and
dosage forms that contain little, if any, lactose or other mono- or
di-saccharides. As used herein, the term "lactose-free" means that the
amount of lactose present, if any, is insufficient to substantially
increase the degradation rate of an active ingredient.

[0125] Lactose-free compositions can comprise excipients that are well
known in the art and are listed, for example, in the U.S. Pharmacopeia
(USP) 25-NF20 (2002). In general, lactose-free compositions comprise
active ingredients, a binder/filler, and a lubricant in pharmaceutically
compatible and pharmaceutically acceptable amounts. In one embodiment,
lactose-free dosage forms comprise active ingredients, microcrystalline
cellulose, pre-gelatinized starch, and magnesium stearate.

[0126] Also provided are anhydrous pharmaceutical compositions and dosage
forms comprising active ingredients, since water can facilitate the
degradation of some compounds. For example, the addition of water (e.g.,
5%) is widely accepted in the pharmaceutical arts as a means of
simulating long-term storage in order to determine characteristics such
as shelf-life or the stability of formulations over time. See, e.g., Jens
T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel
Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heat accelerate
the decomposition of some compounds. Thus, the effect of water on a
formulation can be of great significance since moisture and/or humidity
are commonly encountered during manufacture, handling, packaging,
storage, shipment, and use of formulations.

[0127] Anhydrous pharmaceutical compositions and dosage forms can be
prepared using anhydrous or low moisture containing ingredients and low
moisture or low humidity conditions. Pharmaceutical compositions and
dosage forms that comprise lactose and at least one active ingredient
that comprises a primary or secondary amine are preferably anhydrous if
substantial contact with moisture and/or humidity during manufacturing,
packaging, and/or storage is expected.

[0128] An anhydrous pharmaceutical composition should be prepared and
stored such that its anhydrous nature is maintained. Accordingly,
anhydrous compositions are, in one embodiment, packaged using materials
known to prevent exposure to water such that they can be included in
suitable formulary kits. Examples of suitable packaging include, but are
not limited to, hermetically sealed foils, plastics, unit dose containers
(e.g., vials), blister packs, and strip packs.

[0129] Also provided are pharmaceutical compositions and dosage forms that
comprise one or more compounds that reduce the rate by which an active
ingredient will decompose. Such compounds, which are referred to herein
as "stabilizers," include, but are not limited to, antioxidants such as
ascorbic acid, pH buffers, or salt buffers.

[0130] Like the amounts and types of excipients, the amounts and specific
types of active ingredients in a dosage form may differ depending on
factors such as, but not limited to, the route by which it is to be
administered to patients. In one embodiment, dosage forms comprise a
compound provided herein in an amount of from about 0.10 to about 500 mg.
In other embodiments, dosage forms comprise a compound provided herein in
an amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50,
100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.

[0131] In other embodiments, dosage forms comprise the second active
ingredient in an amount of 1 to about 1000 mg, from about 5 to about 500
mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. Of
course, the specific amount of the second active agent will depend on the
specific agent used, the diseases or disorders being treated or managed,
and the amount(s) of a compound provided herein, and any optional
additional active agents concurrently administered to the patient.

5.4.1 Oral Dosage Forms

[0132] Pharmaceutical compositions that are suitable for oral
administration can be provided as discrete dosage forms, such as, but not
limited to, tablets (e.g., chewable tablets), caplets, capsules, and
liquids (e.g., flavored syrups). Such dosage forms contain predetermined
amounts of active ingredients, and may be prepared by methods of pharmacy
well known to those skilled in the art. See generally, Remington's
Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).

[0133] Oral dosage forms provided herein are prepared by combining the
active ingredients in an intimate admixture with at least one excipient
according to conventional pharmaceutical compounding techniques.
Excipients can take a wide variety of forms depending on the form of
preparation desired for administration. For example, excipients suitable
for use in oral liquid or aerosol dosage forms include, but are not
limited to, water, glycols, oils, alcohols, flavoring agents,
preservatives, and coloring agents. Examples of excipients suitable for
use in solid oral dosage forms (e.g., powders, tablets, capsules, and
caplets) include, but are not limited to, starches, sugars,
micro-crystalline cellulose, diluents, granulating agents, lubricants,
binders, and disintegrating agents.

[0134] In one embodiment, oral dosage forms are tablets or capsules, in
which case solid excipients are employed. In another embodiment, tablets
can be coated by standard aqueous or nonaqueous techniques. Such dosage
forms can be prepared by any of the methods of pharmacy. In general,
pharmaceutical compositions and dosage forms are prepared by uniformly
and intimately admixing the active ingredients with liquid carriers,
finely divided solid carriers, or both, and then shaping the product into
the desired presentation if necessary.

[0135] For example, a tablet can be prepared by compression or molding.
Compressed tablets can be prepared by compressing in a suitable machine
the active ingredients in a free-flowing form such as powder or granules,
optionally mixed with an excipient. Molded tablets can be made by molding
in a suitable machine a mixture of the powdered compound moistened with
an inert liquid diluent.

[0137] Suitable forms of microcrystalline cellulose include, but are not
limited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICEL
RC-581, AVICEL-PH-105 (available from FMC Corporation, American Viscose
Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. An
specific binder is a mixture of microcrystalline cellulose and sodium
carboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or low
moisture excipients or additives include AVICEL-PH-103® and Starch
1500 LM.

[0138] Examples of fillers suitable for use in the pharmaceutical
compositions and dosage forms provided herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and
mixtures thereof. The binder or filler in pharmaceutical compositions is,
in one embodiment, present in from about 50 to about 99 weight percent of
the pharmaceutical composition or dosage form. Disintegrants may be used
in the compositions to provide tablets that disintegrate when exposed to
an aqueous environment. Tablets that contain too much disintegrant may
disintegrate in storage, while those that contain too little may not
disintegrate at a desired rate or under the desired conditions. Thus, a
sufficient amount of disintegrant that is neither too much nor too little
to detrimentally alter the release of the active ingredients may be used
to form solid oral dosage forms. The amount of disintegrant used varies
based upon the type of formulation, and is readily discernible to those
of ordinary skill in the art. In one embodiment, pharmaceutical
compositions comprise from about 0.5 to about 15 weight percent of
disintegrant, or from about 1 to about 5 weight percent of disintegrant.

[0142] Active ingredients provided herein can be administered by
controlled release means or by delivery devices that are well known to
those of ordinary skill in the art.

[0143] Examples include, but are not limited to, those described in U.S.
Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719,
5,674,533, 5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476,
5,354,556, and 5,733,566, each of which is incorporated herein by
reference. Such dosage forms can be used to provide slow or
controlled-release of one or more active ingredients using, for example,
hydropropylmethyl cellulose, other polymer matrices, gels, permeable
membranes, osmotic systems, multilayer coatings, microparticles,
liposomes, microspheres, or a combination thereof to provide the desired
release profile in varying proportions. Suitable controlled-release
formulations known to those of ordinary skill in the art, including those
described herein, can be readily selected for use with the active agents
provided herein. In one embodiment, provided are single unit dosage forms
suitable for oral administration such as, but not limited to, tablets,
capsules, gelcaps, and caplets that are adapted for controlled-release.

[0144] In one embodiment, controlled-release pharmaceutical products
improve drug therapy over that achieved by their non-controlled
counterparts. In another embodiment, the use of a controlled-release
preparation in medical treatment is characterized by a minimum of drug
substance being employed to cure or control the condition in a minimum
amount of time. Advantages of controlled-release formulations include
extended activity of the drug, reduced dosage frequency, and increased
patient compliance. In addition, controlled-release formulations can be
used to affect the time of onset of action or other characteristics, such
as blood levels of the drug, and can thus affect the occurrence of side
(e.g., adverse) effects.

[0145] In another embodiment, the controlled-release formulations are
designed to initially release an amount of drug (active ingredient) that
promptly produces the desired therapeutic or prophylactic effect, and
gradually and continually release of other amounts of drug to maintain
this level of therapeutic or prophylactic effect over an extended period
of time. In one embodiment, in order to maintain a constant level of drug
in the body, the drug can be released from the dosage form at a rate that
will replace the amount of drug being metabolized and excreted from the
body. Controlled-release of an active ingredient can be stimulated by
various conditions including, but not limited to, pH, temperature,
enzymes, water, or other physiological conditions or compounds.

5.4.3 Parenteral Dosage Forms

[0146] Parenteral dosage forms can be administered to patients by various
routes including, but not limited to, subcutaneous, intravenous
(including bolus injection), intramuscular, and intraarterial. In some
embodiments, administration of a parenteral dosage form bypasses
patients' natural defenses against contaminants, and thus, in these
embodiments, parenteral dosage forms are sterile or capable of being
sterilized prior to administration to a patient. Examples of parenteral
dosage forms include, but are not limited to, solutions ready for
injection, dry products ready to be dissolved or suspended in a
pharmaceutically acceptable vehicle for injection, suspensions ready for
injection, and emulsions.

[0147] Suitable vehicles that can be used to provide parenteral dosage
forms are well known to those skilled in the art. Examples include, but
are not limited to: Water for Injection USP; aqueous vehicles such as,
but not limited to, Sodium Chloride Injection, Ringer's Injection,
Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated
Ringer's Injection; water-miscible vehicles such as, but not limited to,
ethyl alcohol, polyethylene glycol, and polypropylene glycol; and
non-aqueous vehicles such as, but not limited to, corn oil, cottonseed
oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and
benzyl benzoate.

[0148] Compounds that increase the solubility of one or more of the active
ingredients disclosed herein can also be incorporated into the parenteral
dosage forms. For example, cyclodextrin and its derivatives can be used
to increase the solubility of a compound provided herein. See, e.g., U.S.
Pat. No. 5,134,127, which is incorporated herein by reference.

[0150] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide topical and mucosal dosage forms
encompassed herein are well known to those skilled in the pharmaceutical
arts, and depend on the particular tissue to which a given pharmaceutical
composition or dosage form will be applied. In one embodiment, excipients
include, but are not limited to, water, acetone, ethanol, ethylene
glycol, propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl
palmitate, mineral oil, and mixtures thereof to form solutions, emulsions
or gels, which are non-toxic and pharmaceutically acceptable.
Moisturizers or humectants can also be added to pharmaceutical
compositions and dosage forms. Examples of additional ingredients are
well known in the art. See, e.g., Remington's Pharmaceutical Sciences,
16th and 18th eds., Mack Publishing, Easton Pa. (1980 & 1990).

[0151] The pH of a pharmaceutical composition or dosage form may also be
adjusted to improve delivery of one or more active ingredients. Also, the
polarity of a solvent carrier, its ionic strength, or tonicity can be
adjusted to improve delivery. Compounds such as stearates can also be
added to pharmaceutical compositions or dosage forms to alter the
hydrophilicity or lipophilicity of one or more active ingredients so as
to improve delivery. In other embodiments, stearates can serve as a lipid
vehicle for the formulation, as an emulsifying agent or surfactant, or as
a delivery-enhancing or penetration-enhancing agent. In other
embodiments, salts, solvates, prodrugs, clathrates, or stereoisomers of
the active ingredients can be used to further adjust the properties of
the resulting composition.

5.5 Kits

[0152] In one embodiment, active ingredients provided herein are not
administered to a patient at the same time or by the same route of
administration. In another embodiment, provided are kits which can
simplify the administration of appropriate amounts of active ingredients.

[0153] In one embodiment, a kit comprises a dosage form of a compound
provided herein. Kits can further comprise one or more second active
ingredients as described herein, or a pharmacologically active mutant or
derivative thereof, or a combination thereof.

[0154] In other embodiments, kits can further comprise devices that are
used to administer the active ingredients. Examples of such devices
include, but are not limited to, syringes, drip bags, patches, and
inhalers.

[0155] Kits can further comprise cells or blood for transplantation as
well as pharmaceutically acceptable vehicles that can be used to
administer one or more active ingredients. For example, if an active
ingredient is provided in a solid form that must be reconstituted for
parenteral administration, the kit can comprise a sealed container of a
suitable vehicle in which the active ingredient can be dissolved to form
a particulate-free sterile solution that is suitable for parenteral
administration. Examples of pharmaceutically acceptable vehicles include,
but are not limited to: Water for Injection USP; aqueous vehicles such
as, but not limited to, Sodium Chloride Injection, Ringer's Injection,
Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated
Ringer's Injection; water-miscible vehicles such as, but not limited to,
ethyl alcohol, polyethylene glycol, and polypropylene glycol; and
non-aqueous vehicles such as, but not limited to, corn oil, cottonseed
oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and
benzyl benzoate.

6. EXAMPLES

[0156] Certain embodiments are illustrated by the following non-limiting
examples.

[0173] (3aR,6aS)-3a-(3,4-Dichlorophenyl)octahydrocyclopenta[c]pyrrole was
made using similar procedures, using
(3aR,6aS)-3a-(3,4-dichlorophenyl)-2-methyloctahydrocyclopenta[c]pyrrole
as a starting compound.

[0182] The compounds disclosed herein were tested for their inhibition of
functional uptake of serotonin (5-HT), norepinephrine (NE), and dopamine
(DA), using recombinant human transporters, as described herein below.
Compounds were initially tested at 10 μM in duplicate. Compounds
showing equal to or higher than 50% inhibition of uptake were further
tested at 10 different concentrations in duplicate in order to obtain
full inhibition curves. IC50 values (concentration inhibiting
control activity by 50%) were then determined by nonlinear regression
analysis of the inhibition curves.

[0183] Inhibition of human serotonin reuptake transporter was assayed
using the recombinant human serotonin transporter expressed in HEK-293
cells using a method substantially similar to that described in Gu H et
al., J. Biol. Chem. 1994, 269 (10): 7124-7130, incorporated herein by
reference. HEK-293 cells expressing human serotonin transporter were
plated before the assay. Test compound and/or vehicle was preincubated
with cells in modified HEPES buffer pH 7.1 or pH 7.4 for 20 minutes at 18
to 25 ° C., and 65 nM [3H]serotonin was then added for an
additional timed incubation period (ten to thirty minutes). Cells with
internalized [3H]serotonin were washed, and the amount of tritium
taken into cells is counted using a liquid scintillation counter to
determine [3H]serotonin uptake. Non-specific binding of tritium was
measured in a control reaction containing 10 μM fluoxetine, and was
subtracted from the counts for assays to correct for non-specific binding
of tritium. Reduction of [3H]serotonin uptake by 50 percent or more
relative to an uninhibited control reaction indicates significant
inhibitory activity. Compounds were screened at 10, 1, 0.1, 0.01 and
0.001 μM.

[0184] Inhibition of human norepinephrine reuptake transporter was assayed
using the recombinant human norepinephrine transporter expressed in
either HEK293 or MDCK cells using a method substantially similar to that
described in Galli A et al., J. Exp. Biol. 198: 2197-2212 (1995),
incorporated herein by reference. The cells were plated before the assay.
Test compound and/or vehicle was preincubated with cells in modified
HEPES buffer pH 7.1 or pH 7.4 for 20 minutes at 18 to 25 ° C.
Following the preincubation, 25 nM [3H]norepinephrine was added for
an additional timed incubation period (10 to 20 minutes). After the cells
were washed to remove [3H]norepinephrine not internalized, the cells
were lysed, and the amount of tritium in the cell lysate was measured
using a liquid scintillation counter to determine [3H]norepinephrine
uptake. Non-specific binding of tritium was measured in a control
reaction containing 10 μM imipramine (or 10 μM nisoxetine), and was
subtracted from the counts for assays to correct for non-specific binding
of tritium. Reduction of [3H]norepinephrine uptake by 50 percent or
more relative to an uninhibited control reaction indicates significant
inhibitory activity. Compounds were screened at 10, 1, 0.1, 0.01 and
0.001 μM.

6.2.3 Dopamine Functional Uptake Assay for Human Reuptake Transporter

[0185] Inhibition of human dopamine reuptake transporter was assayed using
the recombinant human dopamine transporter expressed in either CHO-Kl or
HEK293 cells using a method substantially similar to that described in
Pristupa, Z. B. et al., Mol. Pharmacol. 45: 125-135 (1994), incorporated
herein by reference. Either CHO-K1 or HEK293 cells expressing human
recombinant dopamine transporter were plated before the assay. Test
compound and/or vehicle was preincubated with cells in modified HEPES
buffer pH 7.1 or pH 7.4 for 20 minutes at 18 to 25 ° C., and 50 nM
[3H]dopamine was then added for an additional timed incubation
period (10 to 30 minutes). After washing the cells to remove
[3H]dopamine not internalized, the cells were lysed, and the amount
of tritium in the lysate was measured using a liquid scintillation
counter to determine [3H]dopamine uptake. Non-specific binding of
tritium was measured in a control reaction containing 10 μM
nomifensine, and was subtracted from the counts for assays to correct for
non-specific binding of tritium. Reduction of [3H]dopamine uptake by
50 percent or more relative to an uninhibited control reaction indicates
significant inhibitory activity. Compounds were screened at 10, 1, 0.1,
0.01 and 0.001 μM.

[0189] The liver is the main organ of drug metabolism in the body. Certain
compounds provided herein were tested for microsomal stability using the
following procedures:

[0190] Subcellular fractions such as liver microsomes are useful in vitro
models of hepatic clearance. The human or mouse microsomes were incubated
with the test compounds at 37° C. in the presence of the
co-factor, NADPH, which initiated the reaction. The reaction was
terminated by the addition of methanol. Following centrifugation, the
supernatant was analyzed on the LC-MS/MS. The disappearance of test
compound was monitored over a 45 minute time period.

[0192] Effects of
(3aR,6aS)-3a-(3,4-Dichlorophenyl)octahydrocyclopenta[c]pyrrole on acute
and persistent inflammatory pain were evaluated in male rats. Pain was
induced experimentally by application of a chemical irritant, formalin,
which results in a biphasic behavioral response that includes both early
(Phase 1, 0-9 minutes) and late (Phase 2, 10-60 minutes) phase flinching
behavior. The early phase response is considered to be the result of
C-fiber activation while the late phase appears to be dependent on the
combination of an inflammatory response in the tissue and functional
changes in the dorsal horn of the spinal cord.

6.4.1 Procedures

[0193] Male rats (Sprague-Dawley, 272-315 g, Harlan) were housed 4 animals
per cage in a temperature-controlled environment on a 12-hour light-dark
cycle with food and water available ad libitum. Animals were allowed to
acclimate to the facility for at least 5 days before testing. On the day
of the study, a flexible, light-weight, `C`-shaped metal band was applied
to one hind paw and the rat was dosed orally (PO, 3 mL/kg, via gavage) or
intraperitoneally (IP, 1 mL/kg) with vehicle (50 mM acetate buffer (pH
4.5)), (3aR,6aS)-3a-(3,4-dichlorophenyl)octahydrocyclopenta[c]pyrrole or
gabapentin.
(3aR,6aS)-3a-(3,4-Dichlorophenyl)octahydrocyclopenta[c]pyrrole was
administered at 3, 10 and 30 mg/kg PO in 50 mM acetate buffer (pH 4.5)
vehicle. Gabapentin (AvaChem Scientific) was administered at 100 mg/kg IP
in saline vehicle as a positive control. Sixty minutes after compound
administration, animals were administered a dilute formalin solution (5%,
50 μL) into the dorsal aspect of the hind paw with the `C`-shaped
metal band and then immediately placed in individual test cylinders
(Automated Nociception Analyzer, UCSD, San Diego, Calif.).
Formalin-induced flinching behavior was recorded for 60 minutes.

6.4.2 Results

[0194] Formalin administration resulted in a biphasic flinch response, in
which the sum of behavior was greater in phase II (10-60 minutes post
formalin) compared to phase I (0-9 minutes post formalin).
(3aR,6aS)-3a-(3,4-Dichlorophenyl)octahydrocyclopenta[c] pyrrole
administration resulted in a significant, dose-related decrease in
flinching behavior during phases I and II. Gabapentin administration
resulted in a significant and selective attenuation of phase II
formalin-induced flinching behavior.

[0195] As shown in FIG. 3, acute oral administration of
(3aR,6aS)-3a-(3,4-Dichlorophenyl)octahydrocyclopenta[c]pyrrole
significantly and dose-dependently attenuated formalin-induced flinching
behavior in a non-selective manner when tested in naive male rats up to
30 mg/kg. The robustness of the assay was confirmed by the significant
and selective attenuation of phase II formalin-induced flinching behavior
by the positive control, gabapentin. These results indicate that
(3aR,6aS)-3a-(3,4-Dichlorophenyl)octahydrocyclopenta[c]pyrrole
effectively reduced acute and persistent inflammatory pain in rats and,
thus, indicates the compound's potential efficacy in relieving pain.

[0196] The embodiments described above are intended to be merely
exemplary, and those skilled in the art will recognize, or will be able
to ascertain using no more than routine experimentation, numerous
equivalents of specific compounds, materials, and procedures. All such
equivalents are considered to be within the scope of the disclosure and
are encompassed by the appended claims.

[0197] All of the patents, patent applications and publications referred
to herein are incorporated herein in their entireties. Citation or
identification of any reference in this application is not an admission
that such reference is available as prior art to this application. The
full scope of the disclosure is better understood with reference to the
appended claims.

Patent applications by Fengjiang Wang, Northborough, MA US

Patent applications by Liming Shao, Lincoln, MA US

Patent applications by Michael C. Hewitt, Somerville, MA US

Patent applications by Scott C. Malcolm, Hopkinton, MA US

Patent applications in class Bicyclo ring system having the five-membered hetero ring as one of the cyclos

Patent applications in all subclasses Bicyclo ring system having the five-membered hetero ring as one of the cyclos